Several succinimide derivatives produce renal damage (acute tubular necrosis, interstitial nephritis) in humans and/or animals. The proposed study is an investigation of (a) the structural requirements for nephrotoxicity, (b) the possible formation of toxic metabolites, and (c) some of the potential cellular targets of succinimides. Nephrotoxicity will be monitored in acute and subhronic structural comparative studies by measuring a variety of urinary excretion parameters (volume, content, pH, osmolality), in vitro accumulation of organic ions by renal cortical slices, histochemistry (alkaline phosphatase, glucose-6-phosphatase and succinic dehydrogenase) and histology (light and electron microscopy). The formation of toxic metabolites will be investigated using enzyme induction and inhibition studies, glutathione depletion studies, quantitation of covalent binding to renal proteins and structural modification of a nephrotoxic succinimide. If maleimide metabolites are produced, they will be quantitated and identified using TLC, HPLC and GC/MS. An initial study of renal accumulation (gross and subcellular) of succinimides will be conducted using (14C) N-(3,5-dichlorophenyl) succinimide. Preliminary studies of the effects of succinimides on renal blood flow, glucose production, the tricarboxylic acid cycle and glutathione levels will be conducted using histochemical, in vivo and in vitro assays. The results obtained in these experiments will further our knowledge in the area of chemical-induced renal disease. The identification of maleimide metabolites would mean the discovery of a new class of toxic biotransformation products. Future studies will attempt to more precisely define the cellular mechanisms of succinimide-induced nephropathy and the nephrotoxic potential of related chemical species.